The clinical objective in treatment of peptic ulcer disease is to decrease gastric acid secretion, based on the principle "no acid, no ulcer." Traditional peptic ulcer disease therapy involves control of diet and the use of antacids and anticholinergics.
There is evidence indicating that histamine may be the final common pathway for stimulation of gastric secretion. This effect of histamine is mediated via H.sub.2 -receptors and is not inhibited by the classical antihistamines, which are H.sub.1 -receptor blockers. A number of specific H.sub.2 -receptor blocking agents (H.sub.2 -receptor antagonists) are now known. These compounds inhibit basal acid secretion, as well as secretion by other known gastric acid stimulants, and are useful in the treatment of peptic ulcers.
Burimamide (IIa) was the first clinically effective H.sub.2 -receptor antagonist. It inhibits gastric secretion in animals and man, but oral absorption is poor.
______________________________________ ##STR2## II ______________________________________ IIa; R.sup.4 = H, Z = CH.sub.2, X = S Burimamide b; R.sup.4 = CH.sub.3, Z = S, X = S Metiamide c; R.sup.4 = CH.sub.3, Z = S, X = NCN Cimetidine ______________________________________
Metiamide (IIb), a subsequently evaluated H.sub.2 antagonist, is more potent than burimamide and is orally active in man. Clinical utility was limited, however, owing to toxicity (agranulocytosis). Cimetidine (IIc) is as effective an H.sub.2 antagonist as metiamide, without producing agranulocytosis, and has recently been marketed as an anti-ulcer drug. The half-life of cimetidine is relatively short, thereby necessitating a therapeutic regimen of multi daily doses of 200-300 mg. tablets. There is thus a need for anti-ulcer agents which are longer acting and/or more potent than cimetidine.
Reviews on the development of H.sub.2 antagonists, including those discussed in the preceding paragraph, may be found in C. R. Ganellin, et al., Federation Proceedings, 35, 1924 (1976), in Drugs of the Future, 1, 13 (1976), and in references cited therein. Relevant patents are as follows:
Belgian Pat. No. 841,814 (Farmdoc 90568X) discloses inhibitors of histamine-stimulated gastric secretion having the formula ##STR3## in which HET is one of eight named heterocyclic rings (including pyridyl) which may be substituted by (lower)alkyl, hydroxyl, amino or halogen; Z is sulfur or CH.sub.2 ; X is S, CHNO.sub.2, NCN or NH; Y is NH.sub.2, (lower)alkylamino, di(lower)alkylamino, (lower)alkoxy, phenylethyl, imidazolylethyl, allyl, trifluoroethyl or (CH.sub.2).sub.n R; n is 1-12; and R is OH, (lower)alkoxy, NH.sub.2 or (lower)alkylamino; provided that, when X is NH, Y is trifluoroethyl or (CH.sub.2).sub.n R; and when X is NCN, Y may not be amino or (lower)alkylamino.
Belgian Pat. No. 804,144 (Farmdoc 19437V) discloses inhibitors of histamine-stimulated gastric acid secretion having the formula ##STR4## in which HET is a 5 or 6 membered heterocyclic ring containing nitrogen (pyridine is named), which may be substituted by alkyl, halogen, CF.sub.3, OH or NH.sub.2 ; m and n are each 0-4 and the sum of m and n is from 2 to 4; Z is sulfur, oxygen, NH or CH.sub.2 ; and R.sub.1 is hydrogen or (lower)alkyl.
U.K. Pat. No. 1,421,792 discloses H.sub.2 -receptor inhibitors of the formula ##STR5## wherein X and Y, which may be the same or different, are hydrogen, nitro, cyano or SO.sub.2 Ar, but may not both be hydrogen; R is hydrogen, (lower)alkyl or Het(CH.sub.2).sub.m Z(CH.sub.2).sub.n ; Z is sulfur or methylene; m is 0, 1 or 2 and n is 2 or 3 provided that the sum of m and n is 3 or 4; Het is an imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole, triazole or thiadiazole ring which is optionally substituted by (lower)alkyl, hydroxy, halogen or amino; and Ar is phenyl, optionally substituted by halogen, methyl or amino.
Belgian Pat. No. 844,504 (Farmdoc 07558Y) discloses H.sub.2 -receptor inhibitors of the formula ##STR6## wherein R.sub.1 is (lower)alkyl or --(CH.sub.2).sub.p A; p is 2-4; A is hydroxy, (lower)alkoxy or dimethylamino; R.sub.2 is hydrogen, (lower)alkyl, (lower)alkoxy, amino, methylamino or halogen; or --OR.sub.1 and R.sub.2 taken together form the group --O(CH.sub.2).sub.q O-- joined to two adjacent carbon atoms of the pyridine ring; q is 1-4; n is 2 or 3; Z is sulfur or --CH.sub.2 --; X is sulfur, CHNO.sub.2, NH, NCN or NOH; and Y is inter alia hydrogen, (lower)alkyl or 2-hydroxyethyl.
U.S. Pat. No. 4,112,234 discloses histamine H.sub.2 -receptor inhibitors of the formula ##STR7## wherein R.sup.1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, and processes for the preparation thereof.
U.S. Pat. No. 4,060,621 discloses histamine H.sub.2 -receptor inhibitors of the formula ##STR8## wherein Het is a pyridyl ring optionally substituted by (lower)alkyl, trifluoromethyl, hydroxyl, halogen or amino; Z is sulfur, oxygen, NH or a methylene group; m is 0, 1 or 2 and n is 2 or 3, the sum of m and n being from 2 to 4; X is COR.sub.3, CSR.sub.3, SO.sub.2 R.sub.4, NCHR.sub.5 or, when Z is methylene, may be nitro; R.sub.3 is (lower)alkyl, (lower)alkoxy or, when Z is sulfur, oxygen or NH, may be amino; R.sub.4 is (lower)alkyl, trifluoromethyl, amino or substituted or unsubstituted aryl, such as phenyl optionally substituted by halogen, (lower)alkyl or amino; R.sub.5 is substituted or unsubstituted aryl, such as phenyl; and R.sub.1 is hydrogen or (lower)alkyl such as methyl; and pharmaceutically acceptable salts thereof. U.S. Pat. No. 3,971,786 contains a substantially identical disclosure.